JP2008531642A - Method for obtaining pharmaceutically active compound irbesartan and synthetic intermediates thereof - Google Patents

Abstract

Irbesartan polymorph with few synthesis steps by coupling intermediate of formula (II) with compound of formula (III), neutralizing its alkaline salt in aqueous medium and recrystallizing the resulting crude product A method of obtaining A is provided. With the above method, protection and deprotection of the tetrazole ring is not necessary, so it is quite interesting to obtain irbesartan on a large industrial scale. The invention also relates to a synthetic intermediate of formula (II).

Description

Background of the Invention

The present invention relates to a method for obtaining pharmaceutically active compounds. The present invention also relates to synthetic intermediates useful for obtaining the pharmaceutically active compounds and methods useful for obtaining the intermediates.

  Specifically, the present invention relates to a method for obtaining Irbesartran polymorph A useful for the manufacture of a medicament for the treatment of arterial hypertension or heart failure.

Background Art Irbesartran is a known angiotensin II receptor antagonist that is an octapeptide produced by the action of angiotensin converting enzyme and having a significant effect on blood pressure. The structure of irbesartan is shown in the following formula (I):

  The synthesis of irbesartan is described in particular in US Pat. No. 5,270,317 and US Pat. No. 5,559,233. The third reaction step from the end is the reaction of the cyano group of the biphenyl ring with an azide such as tributyltin azide. US Pat. No. 5,270,317 discloses reaction times up to 210 hours.

  US Pat. No. 5,629,331 describes the precursor 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl) methyl] -1,3-diaza- [4 in an aprotic dipolar solvent. , 4] non-1-en-4-one and the synthesis of irbesartan from sodium azide and triethylamine hydrochloride, neutralization of one of its alkaline salts in an aqueous medium, and subsequent acquisition of Form A by recrystallization is also described. ing. Although aprotic dipolar solvents such as N-methylpyrrolidone have relatively high boiling points and can be difficult to remove, the use of azides involves safety hazards.

  WO 2004/065383 also discloses 2- (1-trityl-1H-tetrazol-5-yl) phenylboronic acid and 2-butyl-3- (4′-bromobenzyl)-under Suzuki coupling conditions. The synthesis of irbesartan tritylate by reacting 1,3-diazospiro [4,4] non-1-en-4-one is described. The product thus obtained is then exposed to acidic conditions to hydrolyze the trityl group of the tetrazole ring, and finally irbesartan is obtained. One negative aspect of the above approach is the use of a bulky protecting group such as trityl, which greatly increases the molecular weight of the last synthetic intermediate, which in turn increases the molecular weight of the last synthetic intermediate to irbesartan. The dramatic reduction in the final hydrolysis provided reduces the atomic efficiency of the process. This results in a significant amount of residual product and increases the number of synthesis steps in the process.

  DE 43 13 747, DE 4407488, U.S. Pat. No. 5,596,006, EP 594022 and WO 9609301 contain an aryl halide and 2 in the presence of a palladium catalyst. The synthesis of other biphenyl compounds by reacting-(1H-tetrazol-5-yl) phenylboronic acid is described.

  Therefore, there is a continuing need for safe and environmentally friendly high yield methods for obtaining irbesartan with fewer synthetic steps. Furthermore, it should be possible to apply the method on an industrial scale.

Summary of the Invention

  The first aspect of the present invention is to provide a method for obtaining irbesartan polymorph A that can be obtained quickly and in high yield.

  This method is also a clean method from an environmental point of view, and does not require the use of an aprotic dipolar solvent that has a relatively high boiling point and may be difficult to remove, such as azide or N-methylpyrrolidone. Safer.

  Even more advantageously, the method defined by the first aspect of the present invention does not use a protecting group for the tetrazole ring of the compound of formula (III). This is in favor of what is understood to be the atomic efficiency of the process, coupled with the fact that the last synthetic step is a catalytic reaction, i.e. from each starting reagent incorporated into the desired product. The atomic ratio is optimal, which indicates that the amount of residue that is itself treated is considerably reduced.

  According to a first aspect of the present invention, an intermediate of formula (II) is coupled with a compound of formula (III), one of its alkaline salts is neutralized in an aqueous medium, and the resulting crude product A method is provided for obtaining irbesartan polymorph A with fewer synthetic steps by recrystallizing the product. The use of the above method eliminates the need for protection and deprotection of the tetrazole ring and is therefore quite advantageous for obtaining irbesartan on a large industrial scale.

  The above method also greatly simplifies the process of isolating and purifying the product. This method eliminates the need for extraction with toluene, which is necessary to remove N-methylpyrrolidone and other organic impurities from the aqueous alkaline salt solution of the product. This method provides environmental improvements by using a single organic solvent that is immiscible with water, such as ethyl acetate. Intermediate crystallization of the crude product is also eliminated prior to final crystallization to obtain the desired polymorph A.

  The second aspect of the present invention is a synthetic intermediate defined by formula (II).

  A third aspect of the present invention is to provide a method for obtaining a synthetic intermediate of formula (II).

  A fourth aspect of the present invention is to provide an alternative method for obtaining a synthetic intermediate of formula (II).

  The fifth aspect of the present invention is to provide yet another improved method for obtaining a synthetic intermediate of formula (II).

Definitions The term “organic base” refers to triethylamine, diisopropylamine (DIPEA), 1,4-diazabicyclo [2,2,2] octane (DABCO), morpholine, and other ammonia derivatives, including one or more hydrogens. Is taken to mean substituted by an alkyl or aryl group.

  The term “inorganic base” means a Group I or Group II metal hydroxide or carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, or potassium fluoride or It is understood to mean potassium phosphate.

  The term “biphasic system” means a reaction medium comprising two liquid phases formed by a first and second solvent immiscible with each other, or a system formed by a liquid phase and a solid phase. It is understood as a thing. The first is an organic solvent. Preferred but not limited examples include 1,2-dimethoxyethane (DME), diethoxymethane (DEM), tetrahydrofuran (THF), hydrocarbons (eg, heptane, cyclohexane, methylcyclohexane, toluene, xylene, tetralin, or Decalin), or a mixture thereof. The second solvent is water, preferably containing an inorganic base. Another two-phase system is the use of at least one solvent selected from the first and second solvents described above and a solid inorganic base.

The term “palladium catalyst” refers to a reaction medium that can be homogeneous or soluble in a reaction medium such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₄ , Pd (AcO) ₂ , or Pd / C. It is understood that it means a compound of palladium that can be heterogeneous or insoluble.

  The term “ligand” refers to an organic compound of the phosphine or amine type that can be coordinated and activated to a palladium species that catalyzes the desired reaction, eg, triphenylphosphine, diphenylphosphine ethylene (DPPE), bis -Diphenylphosphine ferrocene (DPPF), tri- (t-butyl) phosphine, tri- (o-tolyl) phosphine, tricyclohexylphosphine, 3,3 ', 3' '-phosphinidin tris (benzenesulfonic acid) [3 , 3 ', 3 "-phosphinidinatris (benzene-sulphonate)] is understood to mean the trisodium salt (TPPTS).

Detailed description of the invention

The present invention has the object of providing a novel process which can obtain irbesartan of the following formula (I) in good yield and which is not problematic from the safety or environmental aspects:

有機極性溶媒もしくは水性溶媒、水と水混和性溶媒との混合物、または二相系から選択される溶媒媒質中において、式（III）の化合物のテトラゾール環と塩を形成することができる有機塩基または無機塩基の存在下にて、２５〜１５０℃の温度で、パラジウム触媒と必要に応じてリガンドを用いて行って、有機塩基塩もしくは無機塩基塩の水溶液の形態の下式（Ｉ）のイルベルサルタンを得、
（ｂ） 上記アルカリ性水溶液をｐＨ４．８〜５．２の酸性にして、得られる沈澱を濾過し、
（ｃ） 段階（ｂ）の生成物を、有機溶媒またはそれと水との混合物の存在下にて再結晶させ、下記のＸ線回折スペクトルを有するイルベサルタン多形体Ａを得る
ことを特徴とする。 A method for obtaining irbesartan or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention comprises:
(A) A coupling reaction of a compound of the following formula (II) and 2- (1H-tetrazol-5-yl) phenylboronic acid of the following formula (III):

An organic base capable of forming a salt with the tetrazole ring of the compound of formula (III) in a solvent medium selected from an organic polar solvent or an aqueous solvent, a mixture of water and a water-miscible solvent, or a two-phase system, or In the presence of an inorganic base, the reaction is carried out at a temperature of 25 to 150 ° C. using a palladium catalyst and, if necessary, a ligand. Get sultan,
(B) acidifying the alkaline aqueous solution to pH 4.8 to 5.2, and filtering the resulting precipitate;
(C) The product of step (b) is recrystallized in the presence of an organic solvent or a mixture thereof with water to obtain irbesartan polymorph A having the following X-ray diffraction spectrum.

  Advantageously, this coupling is performed without the need to use a protecting group for the tetrazole ring of the compound of formula (III). The reaction is carried out in the presence of an organic or inorganic base capable of forming a salt with the tetrazole ring and in the presence of a catalytic amount of a palladium compound. The reaction is carried out in an organic polar or aqueous solvent, or a mixture of water and a water miscible solvent, or a two-phase system at a temperature of 25 ° C to 150 ° C, preferably 50 ° C to 120 ° C, and even more preferably 70 ° C to 90 ° C. Can be done.

  Preferably, in step (a), the solvent medium is selected from the solvents THF, DME, DEM, toluene, xylene, methanol, ethanol, propanol, decalin and water, or mixtures thereof, and the organic base is TEA, DIPEA, DABCO. , Morpholine and other ammonia derivatives, wherein one or more hydrogens are selected from alkyl or aryl groups such as ethyl, isopropyl, benzyl or phenyl, the inorganic base being sodium carbonate, potassium carbonate , Cesium carbonate, sodium hydroxide, potassium hydroxide, potassium fluoride or potassium phosphate.

This coupling can be performed in a homogeneous phase when the palladium compound is soluble in the reaction medium, such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₄ , Pd (AcO) ₂ , and the palladium compound is in a homogeneous phase. When it is insoluble in the reaction medium as in / C, it can be carried out in a heterogeneous phase. When using Pd / C, the coupling reaction involves a catalytic amount of a ligand, preferably a phosphine type, especially triphenylphosphine or a water-soluble phosphine such as 3,3 ′, 3 ″ -phosphinidin tris ( The presence of the trisodium salt of [benzenesulfonic acid) [3,3 ', 3 "-phosphinidinatris (benzene-sulphonate)] or the sodium salt of diphenylphosphinebenzene-3-sulfonic acid is required. These last ones provide the advantage that the reaction can be carried out using water as a solvent.

  Preferably, in step (c), the organic solvent is at least one alcohol such as methanol, ethanol, propanol or isopropanol, one ester such as ethyl acetate or isopropyl acetate, tetrahydrofuran, dioxane, dimethoxyethane or diisopropyl ether. Is selected from one kind of ether, butanone, a ketone such as methyl isopropyl ketone or methyl isobutyl ketone, or a hydrocarbon such as heptane, toluene, xylene.

  Preferably, the solvent selected in step (c) is isopropanol, which increases the purity of the product and improves the recovery.

The second aspect of the present invention is to provide a synthetic intermediate of formula (II):

  By using the synthetic intermediate of formula (II) to obtain irbesartan, it can be obtained in surprisingly high yield, the reaction crude product becomes more pure and the decomposition of the compound of formula (III) This means that the reaction using the synthetic intermediate of formula (II) continues until the starting product is used up.

The synthetic intermediate 2-butyl-3- (4′-iodobenzyl) -1,3-diazospiro [4,4] non-1-en-4-one of formula (II) is It can be prepared by reaction of 2-butyl-1,3-diazospiro [4,4] non-1-en-4-one hydrochloride of formula (IV) with 4-iodobenzyl bromide. :

  The compound 2-butyl-1,3-diazospiro [4,4] non-1-en-4-one of formula (IV) is a commercially available compound. The above reaction occurs in a two-phase system by vigorous stirring for 1 hour at a temperature of 50 ° C. to 120 ° C. in the presence of an inorganic base and in the presence of a phase transfer catalyst. When the reaction is complete, the system is allowed to cool, the phases are separated and the organic phase is evaporated to give the crude product. The crude product is dissolved in a suitable solvent such as ethyl acetate or isopropyl acetate, an equivalent amount of concentrated hydrochloric acid is added thereto, and after filtration, the compound of formula (II) as a highly pure hydrochloride is obtained in very high yield. obtain.

次いで、これを触媒量（１％〜５％）の酢酸、ギ酸、メタンスルホン酸またはトルエンスルホン酸のようなスルホン酸の存在下にてトリメチルオルトバレレートと反応させて、スキーム２に準じて、式（II）の合成中間体を提供する
ことによって得ることもできる。 The compound 2-butyl-3- (4′-iodobenzyl) -1,3-diazospiro [4,4] non-1-en-4-one of formula (II) is prepared in the presence of an organic solvent and a condensing agent. Using 4-iodobenzylamine to amidate the protected 1-amino-cyclopentanocarboxylic acid as tertiary butoxycarbonylamine, as benzyloxycarbonylamine or as pentanoylamine to provide a diamide;
a) providing the compound of formula (II) by cyclization in an acid or thermally catalyzed reaction according to Scheme 1 or b) under acidic conditions or in the presence of hydrogen and a platinum catalyst Deprotecting the protecting group provides 4-iodobenzylamide of 1-amino-1-cyclopentanocarboxylic acid of formula (IX)

This is then reacted with trimethylorthovalerate in the presence of a catalytic amount (1-5%) of acetic acid, formic acid, methanesulfonic acid or sulfonic acid such as toluenesulfonic acid, according to Scheme 2, It can also be obtained by providing a synthetic intermediate of formula (II).

  On the other hand, the compound 2-butyl-3- (4′-iodobenzyl) -1,3-diazospiro [4,4] non-1-en-4-one of formula (II) is in accordance with Scheme 1 below. Obtainable.

Scheme 1

  In the above scheme 1, 1-pentanoylamine-cyclopentanocarboxylic acid (V) (a compound described in G. Winters et al., Il Farmaco, Ed. Sc. 1966, 21, 624) is reacted in a nonpolar solvent. Amidation with 4-iodobenzylamine in the presence of a condensing agent provides the diamide of formula (VI). Suitable solvents for this reaction are dichloromethane, acetonitrile, THF, ethyl acetate, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), especially DMF. A condensing agent is an agent that promotes the reaction between a carboxylic acid and an amine to form an amide. Among those used are dicyclohexylcarbodiimide (DCC), dimethylaminopropylcarbodiimide (WSC), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), benzotriazolyloxy-tris ( Examples include dimethylaminophosphonium hexafluorophosphate (BOP), in particular BOP, which can be cyclized in an acid or thermally catalyzed reaction to give a compound of formula (II). .

  Further, the compound 2-butyl-3- (4′-iodobenzyl) -1,3-diazospiro [4,4] non-1-en-4-one of the formula (II) is in accordance with the following scheme 2. Obtainable.

  1-tert-Butoxycarbonylamine-cyclopentanocarboxylic acid (VII) (compound described in EP Johnson et al., Org. Proc. Res. & Dev. 1998, 2, 238) was treated with 4-iodo under the above conditions. Amidation with benzylamine provides diamide (VIII). Deprotection of the protecting group BOC under acidic conditions provides 4-iodobenzylamide of 1-amino-1-cyclopentanocarboxylic acid of formula (IX). This compound of formula (IX) reacts with trimethylorthovalerate in the presence of a catalytic amount of acid to produce a compound of formula (II).

Scheme 2

  The present invention also provides an alternative method for obtaining a synthetic intermediate of formula (II) that does not require 4-iodobenzylamine, a very expensive reagent that is difficult to obtain.

  The inventors have found that a synthetic intermediate of formula (II) can be prepared by using the compound 4-iodobenzyl bromide, a commercially available reagent at a reasonable price.

二相反応系で相間移動触媒の存在下にて、下式（Ｘ）の１−ペンタノイルアミン−シクロペンタノカルボキサミドと４−ヨードベンジルブロミドとの反応によって、得る

ことを包含する。 The above-mentioned separate method (see the following scheme 3) is the synthesis intermediate of the following formula (II)

Obtained by reaction of 1-pentanoylamine-cyclopentanocarboxamide of the following formula (X) with 4-iodobenzyl bromide in the presence of a phase transfer catalyst in a two-phase reaction system.

Including that.

  Advantageously, one of the phases comprises 1,2-dimethoxyethane (DME), diethoxymethane (DEM), tetrahydrofuran (THF) or an aliphatic or aromatic hydrocarbon and the other phase is The water can include an inorganic base, or the other phase can be a solid inorganic base.

  Also advantageously, prior to reaction with 4-iodobenzyl bromide, the 1-pentanoylamine-cyclopentanocarboxamide of formula (X) becomes an aqueous suspension that can contain an inorganic base. Yes.

Preferably, the inorganic base is selected from KOH, NaOH, LiOH, Na ₂ CO ₃ and K ₂ CO ₃ . Even more preferably, the inorganic base is KOH.

  Advantageously, prior to reaction with 1-pentanoylamine-cyclopentanocarboxamide of formula (X), 4-iodobenzyl bromide is converted to 1,2-dimethoxyethane (DME), diethoxymethane (DEM). ), Tetrahydrofuran (THF), or an aliphatic hydrocarbon such as heptane, cyclohexane or methylcyclohexane, or an aromatic hydrocarbon such as toluene, xylene, decalin or tetralin. Preferably, the aromatic hydrocarbon is toluene.

  The reaction of 1-pentanoylamine-cyclopentanocarboxamide of formula (X) with 4-iodobenzylbromide is a phase transfer such as ammonium or quaternary phosphonium salts, polyethylene glycol derivatives, crown ethers or cryptands. It is carried out in the presence of a catalyst, preferably an acidic sulfate of tetrabutylammonium.

  Scheme 3 according to the present invention is shown below.

Scheme 3

  Advantageously, according to the present invention, irbesartan is applicable on an industrial scale, is more pure from an environmental point of view and has a good chemical yield and high optical performance in a safer manner. Obtained in purity.

  Some examples illustrating preferred embodiments of various aspects of the present invention are given by way of non-limiting illustration of the present invention.

Example 1: Obtaining 2-butyl-3- (4'-iodobenzyl) -1,3-diazospiro [4,4] non-1-en-4-one (II) 2-butyl- 1,3- A solution of diazospiro [4,4] non-1-en-4-one hydrochloride (23.07 g, 100 mmol) and potassium hydroxide (19.8 g) in 100 ml of water was dissolved in 29.7 g of 4-iodobenzyl bromide (100 Mmol) and 3.4 g (10 mmol) of tetrabutylammonium bisulfate in 30 ml of toluene are added and the mixture is heated to reflux for 1 hour. After cooling to 25 ° C., 100 ml of water are added and the phases are separated. 10 ml of concentrated hydrochloric acid are added to the organic phase, 100 ml are evaporated under reduced pressure, 300 ml of ethyl acetate are added and the resulting solid is filtered to give 39.6 g (88%) of the title compound in the form of the hydrochloride.

DSC (min): 82 ℃
IR (KBr, cm ^-1 ): 3500, 3420, 2940, 1770, 1630, 1500.
1H NMR (CDCl ₃ ), [δ] (ppm): 0.80 (t, 3H, CH ₃ ), 1.30-1.50 (m, 2H, -CH ₂ -CH ₃ ), 1.55-1.80 (m, 2H, -CH ₂ -CH ₂ -CH ₃ ), 1.80-2.40 (m, 8H, cyclopentane), 2.95 (t, 2H, CH ₂ -CN), 4.85 (s, 2H, CH ₂ -Ar), 6.95 (d, 2H , H-Ar), 7.75 (d, 2H, H-Ar).

Example 2: Obtaining 4-iodobenzylamide (VI) of 1-pentanoylamine-cyclopentanocarboxylic acid 8.2 g (18.6 mmol) of BOP was added to 1-pentanoylamine-cyclopentanocarboxylic acid. To a suspension of 96 g (18.6 mmol), 4-iodobenzylamine hydrochloride 5.0 g (18.6 mmol) and diisopropylamine 6.5 ml (37.2 mmol) in 40 ml dimethylformamide, Stir for 10 hours. The reaction mixture is poured into a mixture of EtOAc (400 ml) and water (400 ml) and stirred for 30 minutes. After decanting, the organic phase is washed with a saturated solution of sodium bicarbonate (200 ml x 2), a 5% solution of sodium bisulfite (200 ml), a saturated solution of sodium chloride (100 ml), dried over magnesium sulfate and evaporated. Let The residue was recrystallized from 60 ml of toluene to obtain 6.0 g (75%) of the title compound as a white solid.

Melting point = 150-152 ° C
IR (KBr, cm ^-1 ): 3340, 3280, 1660, 1650, 1540.
1H NMR (DMSO-d6), [δ] (ppm): 0.80 (t, 3H, CH ₃ ), 1.10-2.20 (m, 14H), 4.20 (d, 2H, CH ₂ -Ar), 7.05 (d, 2H, H-Ar), 7.60 (d, 2H.H.Ar).

Example 3: Obtaining 2-butyl-3- (4'-iodobenzyl) -1,3-diaza [4,4] non-1-en-4-one (II) (according to Scheme 1)
1.0 g (2.33 mmol) of the compound of Example 2 is heated to 250 ° C. for 2 hours under a nitrogen stream. The product thus obtained was purified by silica gel chromatography, eluting with a 1: 1 mixture of heptane / ethyl acetate to give 400 mg (42%) of the title compound as a colorless oil.

IR (film, cm ^-1 ): 2960, 2860, 1700, 1620, 1460, 1320.
1H NMR (CDCl ₃ ), [δ] (ppm): 0.90 (t, 3H, CH ₃ ), 1.10-2.10 (m, 14H), 2.30 (t, 2H, CH ₂ -CN), 4.60 (s, 2H , CH ₂ -Ar), 6.90 (d, 2H, H-Ar), 7.65 (d, 2H, H-Ar).

Example 4: Obtaining 1-tert-butoxycarbonylamine-cyclopentanocarboxylic acid 4-iodobenzylamide (VIII) According to the method of Example 2, 1.26 g of 1-tert-butoxycarbonylamine-cyclopentanocarboxylic acid Starting from (5.5 mmol), 1.80 g (74%) of the title compound are obtained in the form of a white solid.

Melting point = 185-187 ° C
IR (KBr, cm ^-1 ): 3340, 2980, 1690, 1650, 1520.
1H NMR (DMSO-d6), [δ] (ppm): 1.10-2.10 (m, 17H), 4.20 (d, 2H), 6.90-7.10 (m, 3H), 7.60 (d, 2H), 8.10 (sa , HN).

Example 5: Obtaining 4-iodobenzylamide (IX) of 1-amino-cyclopentanocarboxylic acid 5 ml of trifluoroacetic acid in which 1.40 g (3.15 mmol) of the compound of Example 4 was dissolved in 10 ml of dichloromethane Add to. After 15 minutes, it is poured into a mixture of ethyl acetate (200 ml), a saturated solution of sodium bicarbonate (200 ml) and 20% sodium hydroxide (2.0 ml). The phases are separated and the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated to give 1.0 g (92%) of the title compound as a white solid.

Melting point = 67-69 ℃
IR (KBr, cm ^-1 ): 3400, 2980, 1650, 1510, 1490.
1H NMR (DMSO-d6), [δ] (ppm): 1.30-2.20 (m, 8H, cyclopentane), 4.22 (d, 2H, CH ₂ -Ar), 7.02 (d, 2H, H-Ar), 7.65 (d, 2H, H-Ar), 8.55 (sa, HN).

Example 6: Obtaining 2-butyl-3- (4′-iodobenzyl) -1,3-diaza [4,4] non-1-en-4-one (II) (according to Scheme 2)
A solution of 850 mg (2.47 mmol) of the compound of Example 5, 1.0 ml (5.80 mmol) of trimethylorthovalerate and 0.1 ml (1.75 mmol) of acetic acid in 5 ml of dichloromethane Heat for minutes. After evaporation, the residue is purified by silica gel chromatography, eluting with heptane / ethyl acetate 2: 1. Evaporation of the correct fractions gave 400 mg (39%) of the title compound as a colorless oil with the same spectroscopic data as described in Example 3.

Example 7: 2-Butyl-3- [2 ′-(1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -1,3-diazospiro [4,4] non-1-en-4-one (I) Obtaining (Irbesartan) 2-butyl-3- (4′-iodobenzyl) -1,3-diazospiro [4.4] non-1-en-4-one (II) 2.0 g (4. 9 mmol), 2- (1H-tetrazol-5-yl) phenylboronic acid (III) 1.10 g (4.9 mmol), sodium hydroxide 780 mg (19.6 mmol) and palladium tetrakistriphenylphosphine 283 mg (0 .245 mmol) dissolved in 20 ml of methanol is gently purged with nitrogen for 5 minutes and heated to reflux for 1 hour.

  After cooling to 20 ° C., it is diluted with ethyl acetate (100 ml) and water (50 ml) and 5.0 g of citric acid is added. The phases are separated, the organic phase is evaporated, the residue is purified by silica gel chromatography (eluent dichloromethane / methanol / ammonia 500: 50: 5) and 1.83 g (86%) of white solid compound (I) is obtained. It has gained.

1H NMR (CDCl ₃ ), [δ] (ppm): 0.80 (t, 3H, CH ₃ ), 1.10-1.35 (m, 2H, CH ₂ -CH ₃ ), 1.35-1.60 (m, 2H, CH _2- CH ₂ -CH ₃ ), 1.60-1.95 (m, 8H, cyclopentyl), 2.15 (t, 2H, CH ₂ -CN), 4.60 (s, 2H, CH ₂ -Ar), 7.05 (d, 2H, H- Ar), 7,15 (d, 2H, H-Ar), 7.45 (d, IH, H-Ar), 7.50-7.70 (m, 2H, H-Ar), 7.90 (d, 2H, H-Ar tetrazole (Ortho relative to).

Example 8: 2-Butyl-3- [2 ′-(1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -1,3-diazospiro [4,4] non-1-en-4-one (I) Obtaining (Irbesartan) 2-butyl-3- (4′-iodobenzyl) -1,3-diazospiro [4,4] non-1-en-4-one (II) 2.051 g (5. 0 mmol), 2- (1H-tetrazol-5-yl) phenylboronic acid (III) 1.13 g (5.0 mmol), sodium hydroxide 800 mg (20.0 mmol), triphenylphosphine 262 mg (1.0 mmol) Mmol) and 44 mg (0.25 mmol) of palladium chloride dissolved in 20 ml of methanol are gently purged with nitrogen for 5 minutes and heated to reflux for 1 hour. After cooling to 20 ° C., it is diluted with ethyl acetate (100 ml) and water (50 ml) and 5.0 g of citric acid is added. The phases are separated, the organic phase is evaporated, the residue is purified by silica gel chromatography (eluent dichloromethane / methanol / ammonia 500: 50: 5) and 1.77 g (83%) of white solid compound (I) is obtained. It has gained.

Example 9: 2-Butyl-3- [2 ′-(1H-tetrazol-5-yl) -biphenyl-4-ylmethyl] -1,3-diazospiro [4,4] non-1-en-4-one (I) Obtaining (Irbesartan) 2-butyl-3- (4′-iodobenzyl) -1,3-diazospiro [4,4] non-1-en-4-one (II) 2.0 g (4. 9 mmol), 2- (1H-tetrazol-5-yl) phenylboronic acid (III) 1.10 g (4.9 mmol), sodium hydroxide 780 mg (19.6 mmol), triphenylphosphine 56.5 mg (0 216 mmol) and 420 mg of paste-like 5% Pd / C (0.098 mmol of palladium) in 20 ml of methanol are heated to reflux for 3 hours. After cooling to 20 ° C., it is diluted with ethyl acetate (50 ml) and water (150 ml), the catalyst is filtered off, the phases are separated, and 3N hydrochloric acid is added to the aqueous phase to pH 5.0. This was filtered and the obtained solid was recrystallized from 2-propanol to obtain 1.45 g (69%) of Form A of white solid compound (I) (FIG. 1).

Example 10: Obtaining 2-butyl-3- (4′-iodobenzyl) -1,3-diazospiro [4,4] non-1-en-4-one (II) (according to Scheme 3)
A solution obtained by dissolving 2.97 g (10.0 mmol) of 4-iodobenzyl bromide in 30 ml of toluene was added 2.12 g (10.0 mmol) of 1-pentanoylamine-cyclopentanocarboxamide (X), 1.78 g of KOH. (27.0 mmol) and 0.51 g (1.5 mmol) of TBAHS are added dropwise to a suspension stirred in 10 ml of water. This is stirred at 25 ° C. for 30 minutes and then heated at 70 ° C. for 3 hours. After cooling to 25 ° C., 30 ml of water are added and the phases are separated. The aqueous phase is extracted with 30 ml of toluene and the combined organic phases are washed with a saturated solution of NaCl (30 ml) and evaporated.

  The residue was purified by silica gel chromatography, eluting with a mixture of heptane / ethyl acetate 1: 1 and 2.87 g (70%) of the title compound having the same spectroscopic data as described in Example 1 above was colorless. Obtained as an oil.

  Advantageously, the method of Scheme 3 provides a better yield of the synthetic intermediate of formula (II).

The X-ray-diffraction figure of the A body of compound (I) obtained according to Example 9. FIG.

Claims (42)

A method for obtaining a pharmaceutically active compound, irbesartan or a pharmaceutically acceptable salt thereof, comprising:
(A) A coupling reaction of a compound of the following formula (II) and 2- (1H-tetrazol-5-yl) phenylboronic acid of the following formula (III):

An organic base capable of forming a salt with the tetrazole ring of the compound of formula (III) in a solvent medium selected from an organic polar solvent or an aqueous solvent, a mixture of water and a water-miscible solvent, or a two-phase system, or In the presence of an inorganic base, the reaction is carried out at a temperature of 25 to 150 ° C. using a palladium catalyst and, if necessary, a ligand. Get sultan:

(B) acidifying the alkaline aqueous solution to pH 4.8 to 5.2, and filtering the resulting precipitate;
(C) The product of step (b) is recrystallized in the presence of an organic solvent or a mixture of it and water to obtain irbesartan polymorph A having the following X-ray diffraction spectrum:

Comprising a method.   The process according to claim 1, wherein in step (a), the coupling reaction is carried out at a temperature of 50C to 120C.   The method according to claim 2, wherein the temperature is 70 ° C. to 90 ° C.   The process according to claim 1, wherein in step (a) the solvent medium is selected from the solvents THF, DME, DEM, toluene, xylene, methanol, ethanol, propanol, decalin and water, or mixtures thereof.   The process according to claim 1, wherein in step (a) the organic base is selected from TEA, DIPEA, DABCO, morpholine, and other ammonia derivatives in which one or more hydrogens are replaced by alkyl or aryl groups. .   6. A process according to claim 5, wherein the alkyl or aryl group is selected from ethyl, isopropyl, benzyl or phenyl.   The process according to claim 1, wherein in step (a) the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium fluoride or potassium phosphate.   The process according to claim 1, wherein in step (a) the coupling is carried out in a homogeneous phase when the palladium compound is soluble in the reaction medium or in a heterogeneous phase when the palladium compound is insoluble in the reaction medium. If the palladium compound is soluble in the reaction medium, the palladium _{compound, Pd (PPh 3) 4,} PdCl 2 (PPh 3) 4, Pd (AcO) 2 or is selected from PdCl _2, The method of claim 8 .   If the palladium compound is insoluble in the reaction medium, the palladium compound is selected from palladium compound, Pd / C, or another type of palladium compound supported or immobilized in a polymer or other type of functionalized fiber And the coupling reaction is carried out in the presence of a catalytic amount of a ligand.   11. A process according to claim 10, wherein the ligand is of the phosphine type, preferably triphenylphosphine or water soluble phosphine.   The process according to claim 1, wherein the water-soluble phosphine is the trisodium salt of 3,3 ', 3 "-phosphinidin tris (benzenesulfonic acid).   The process according to claim 1, wherein in step (c) the organic solvent is selected from at least alcohols, esters, ethers, ketones, or hydrocarbons.   14. A process according to claim 13, wherein the alcohol is selected from methanol, ethanol, propanol or isopropanol.   14. A process according to claim 13, wherein the ester is selected from ethyl acetate or isopropyl acetate.   14. A process according to claim 13, wherein the ether is selected from tetrahydrofuran, dioxane, dimethoxyethane, or diisopropyl ether.   14. A process according to claim 13, wherein the ketone is selected from butanone, methyl isopropyl keto, or methyl isobutyl ketone.   14. A process according to claim 13, wherein the hydrocarbon is selected from heptane, toluene or xylene.   In step (c), the product from step (b) is present in the presence of a mixture of organic solvents or a mixture thereof with water, preferably in the presence of a mixture with a water ratio of 1% to 20% by volume. The method according to claim 1, wherein recrystallization is carried out. Synthetic intermediates of formula (II):

. A method for obtaining a synthetic intermediate of formula (II) according to claim 20, comprising
a) 2-butyl-1,3-diazospiro [4,4] non-1-en-4-one hydrochloride of the following formula (IV) and 4-iodobenzyl bromide:

In a two-phase system of toluene / water, benzene / water, cyclohexane / water, methylcyclohexane / water, or other aliphatic or aromatic hydrocarbons, with vigorous stirring in the presence of an inorganic base and a phase transfer catalyst, Reacting at a temperature of 70-120 ° C. under phase transfer conditions;
b) The phases are then separated and the organic phase is evaporated to give the crude product, which is dissolved in an organic solvent and an equivalent amount of concentrated hydrochloric acid to convert the compound of formula (II) below as the hydrochloride salt after filtration. provide

Comprising a method.   The process according to claim 21, wherein in step a) the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.   The process according to claim 21, wherein in step a) the temperature is from 80C to 105C, preferably 90C.   The process according to claim 21, wherein in step b) the organic solvent is selected from acetone, 2-propanol or an alkyl ester, preferably ethyl acetate or isopropyl acetate. A method for obtaining a synthetic intermediate of formula (II) according to claim 20, comprising
1-amino-cyclopentanocarboxylic acid protected with 4-iodobenzylamine, as tertiary butoxycarbonylamine, as benzyloxycarbonylamine or as pentanoylamine in the presence of an organic solvent and a condensing agent Amidation to provide the diamide,
a) cyclization in an acid catalyzed reaction or a thermally catalyzed reaction provides a compound of formula (II), or b) a protecting group under acidic conditions or in the presence of hydrogen and a platinum catalyst Is deprotected to provide 4-iodobenzylamide of 1-amino-1-cyclopentanocarboxylic acid of formula (IX):

This is then reacted with trimethylorthovalerate in the presence of 1% to 5% formic acid, acetic acid, methanesulfonic acid or toluenesulfonic acid to provide a compound of formula (II)

Comprising a method. The amidation of 1-pentanoylamine-cyclopentanocarboxylic acid of the formula (V) with 4-iodobenzylamine occurs in the presence of a condensing agent in an organic solvent to give the diamide of the following formula (VI) Provide

26. The method of claim 25, wherein after cyclization according to step a), a compound of formula (II) is provided.   26. The method of claim 25, wherein the acid catalyzed reaction is carried out at 110 <0> C or 150 <0> C without an acid catalyst. The amidation of 1-tert-butoxycarbonylamine-cyclopentanocarboxylic acid of formula (VII) with 4-iodobenzylamine occurs in the presence of a condensing agent in an organic solvent to give the following formula (VIII) Provides diamide

26. The method of claim 25, wherein this provides a compound of formula (IX) according to step b) and then a compound of formula (II).   29. A process according to any one of claims 25 to 28, wherein the organic solvent is selected from tetrahydrofuran, acetonitrile, N-methylpyrrolidinone, N-ethylpyrrolidinone, DMA, DMF, preferably DMF.   The condensing agent is dicyclohexylcarbodiimide (DCC), dimethylaminopropylcarbodiimide (WSC), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), benzotriazolyloxy-tris (dimethylamino) 29. Process according to any one of claims 25 to 28, selected from phosphonium hexafluorophosphate (BOP), preferably BOP.   The process according to claim 25, wherein the reaction with trimethylorthovalerate is carried out in the presence of formic acid, acetic acid, methanesulfonic acid or toluenesulfonic acid in an amount of 1% to 5%. A method for obtaining a synthetic intermediate of formula (II) according to claim 20, comprising
In the presence of a phase transfer catalyst in a two-phase reaction system, 1-pentanoylamine-cyclopentanocarboxamide of the following formula (X) is reacted with 4-iodobenzyl bromide

Comprising a method.   33. The method of claim 32, wherein the two-phase system comprises two liquid phases, or one liquid phase and one solid phase.   34. One of the liquid phases is 1,2-dimethoxyethane (DME), diethoxymethane (DEM), tetrahydrofuran (THF) or an aliphatic or aromatic hydrocarbon, or includes water. The method described.   35. The method of claim 34, wherein water is used as one of the phases, the water comprising a solution of an inorganic base.   34. The method of claim 33, wherein the solid phase is a solid inorganic base.   36. A process according to claim 32 or 35, wherein, prior to the reaction with 4-iodobenzyl bromide, 1-pentanoylamine-cyclopentanocarboxamide of formula (X) is in an aqueous solution containing an inorganic base.   38. The method of claim 37, wherein the inorganic base is KOH.   35. The method of claim 32, wherein the 4-iodobenzyl bromide is in a solution containing an aliphatic or aromatic hydrocarbon prior to reaction with 1-pentanoylamine-cyclopentanocarboxamide of formula (X).   40. The method of claim 39, wherein the hydrocarbon is toluene.   The process according to claim 32, wherein the phase transfer catalyst is selected from ammonium or quaternary phosphonium salts, polyethylene glycol derivatives, crown ethers or cryptands.   42. The method of claim 41, wherein the phase transfer catalyst is an acidic sulfate of tetrabutylammonium.

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